This is an application for a competitive continuation of a program project that focuses on the role of Calcium Regulation in Brain Aging and Alzheimer's Disease and on basic processes that underlie neuronal vulnerability. During the prior period, investigators in the program project were able to elucidate a number of key changes in calcium regulation in brain cells of aging animals and in models of neurodegeneration/Alzheimer's disease. New evidence was also obtained that such changes in calcium regulation may be directly relevant to neurodegenerative processes. In addition, program project investigators uncovered new leads and performed tests of several hypotheses on the possible causal bases of age-related calcium dysregulation. During the next period, it is proposed to pursue a comprehensive approach to the study of calcium regulation in brain aging and Alzheimer's disease, using advanced technologies for calcium imaging, electrophysiology and molecular biology. The Program Project (PGP) will consist of five projects and one administrative core. The projects will test several hypotheses of the initial causes of calcium dysregulation including the role of steroid hormones (which have specific target sites in brain cells), altered gene expression of function, and brain energy metabolism. Specific neuronal sites of calcium dysregulation that will be examined include membrane ion channels, endoplasmic reticulum, mitochondria, the cytoskeleton and intracellular signaling pathways. In addition, related studies will be conducted directly on autopsy brain tissues from AD and control subjects. The PGP brings together investigators with a natural interest in the mechanisms of calcium regulation and neurotoxicity, and skills in advanced technologies. These investigators will share overlapping models and collaborate extensively on related subjects, thereby ensuring strong cross-fertilization and multi-disciplinary approaches to the key questions under investigation.